Hepcidin and iron regulatory proteins coordinately regulate ferroportin 1 expression in the brain of mice

Abstract

Iron plays an essential role in various cellular metabolic processes of the body.Maintenance of cellular iron homeostasis is particularly important for keeping the normal functions of the cells. Ferroportin 1 (FPN1) is the currently only known iron exporter on the cell membrane. It has been indicated that the regulation of FPN1 in response to the alteration of iron level mainly involves two processes, posttranscriptional repression by iron regulatory proteins (IRPs) and posttranslational degradation by hepcidin, the major iron-sensing hormone. However, whether there is any communication between the two types of regulations or which one plays dominant role has not been reported. In our study with IRP2 −/− mice, we found that knockout of IRP2 increased FPN1 expression in the cerebral cortex of IRP2 −/− mice, whereas the upregulation of FPN1 was more significant in IRP1/IRP2 dual knockdown fibroblasts.Interestingly, we found that the knockout of IRP2 severely affected the regulation effect of hepcidin on FPN1 in mouse brain. FPN1 level decreased dramatically in the brain of wild-type mice injected with hepcidin, but it did not decrease much in IRP2 knockout mice. Further investigation disclosed that the compromised hepcidin-FPN1 regulation in IRP2 −/− cells was directly dependent on the existence of iron-responsive element (IRE) in FPN1 messenger RNA. These results indicate that IRPs and hepcidin coordinately regulate the FPN1 level in mice. This study will provide a more comprehensive understanding of the regulatory mechanisms of FPN1 expression. K E Y W O R D Sferroportin 1 (FPN1), hepcidin, iron metabolism, iron-responsive element (IRE), iron regulatory proteins (IRPs)

Brain iron transport

“…At present, information on the mechanisms involved in iron transport and homeostasis in oligodendrocytes and microglia remains very limited as compared to neurons and astrocytes. In addition, how the expression of iron transport proteins is controlled in the brain under physiological conditions, and the genetic and non‐genetic causes that might lead to misregulation of brain iron metabolism are two key questions that have yet to be answered. A number of studies have provided evidence for the existence of hepcidin in the brain (Wang et al ., ; Wang et al, ; Raha‐Chowdhury et al, ; Pellegrino et al, ; Lu et al, ; Puy et al, ; Vela, ; Wang et al, ). Recent studies have shown that this iron regulatory hormone is also a central player in brain iron homeostasis and has a key role in controlling iron transport in the BBB, and iron uptake and release in astrocytes and neuronal cells (Du et al, , ; Gong et al, ).…”

“…(6) A number of studies have provided evidence for the existence of hepcidin in the brain (Wang et al, 2008a;Wang et al, 2010;Raha-Chowdhury et al, 2015;Pellegrino et al, 2016;Lu et al, 2017;Puy et al, 2018;Vela, 2018;Wang et al, 2019). Recent studies have shown that this iron regulatory hormone is also a central player in brain iron homeostasis and has a key role in controlling iron transport in the BBB, and iron uptake and release in astrocytes and neuronal cells (Du et al, 2011Gong et al, 2016).…”

Retinal Degeneration and Alzheimer’s Disease: An Evolving Link

“…This is achieved by modulating the expression of ferroportin (Fpn), the only known iron export protein. Increased iron saturation of serum transferrin upregulates the secretion of liver hepcidin, which binds Fpn on the plasma membrane of cells and causes its internalization and degradation [ 106 ]. This decreases both iron uptake from the intestine and release from iron stores, reducing the circulating iron.…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…Also, the endoplasmic reticulum stress‐related factor CCAAT/C/EBP homologous protein (CHOP) has been found to promote hepcidin expression by regulating C/EBPα activity in male SD rats with subarachnoid hemorrhage, indicating that the CHOP pathway is one of the routes for control of hepcidin expression in the brain . In addition, the regulation of hepcidin on Fpn1 expression was found to be coordinated with iron regulatory proteins …”